tbuckley/cabot-search huggingface dataset:
P1510: INCIDENCE AND RISK FACTORS OF ACTIVE CARBAPENEM-RESISTANT ENTEROBACTERIACEAE SURVEILLANCE FOR PATIENTS ADMITTED TO HEMATOLOGY DEPARTMENT: A PROPENSITY SCORE MATCHING STUDY.
Authors: Shaozhen Chen, Tingting Xiao, Jinhua Ren, Haojie Zhu, Chenjing Ye, Jingjing Xu, Jianda Hu, Ting Yang
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Carbapenem-resistant Enterobacteriaceae (CRE) infection is an urgent problem associated with mortality for hematological patients. Aims: The aim of this study was to demonstrate the importance of active CRE surveillance in the hematology ward and identify the risk factors for mortality in active CRE surveillance and non-active CRE surveillance patients. Methods: The retrospective cohort study identified 23832 hematological patients between 2019 and 2021. Propensity Score Matching was performed to match underling diseases and admission time in a ratio of 1:1:1 for three groups (detected CRE, undetected CRE and non-active CRE surveillance). Results: The positivity rate of active CRE surveillance among all samples was 2.1% (141/6735) and the incidence rate of detected CRE among all patients received active CRE surveillance was 4.8% (85/1789). The distribution among all the 141 isolates were Klebsiella pneumoniae (66.7%) and Escherichia coli (22.6%) and others (10.8%). The risk factors independently associated with positive result of active CRE surveillance were: accept the hematopoietic stem cell transplantation, hospital LOS ≥ 18 d, central venous catheter, treatment with steroid previous 3 months, exposure to antibiotics (ß-lactam/ß-lactamase inhibitor combinations, Echinocandins) previous 1 month, perianal skin ulceration previous 3 days, albumin < 33.4 g/L and neutropenia ≥ 7d. 26.5% patients in detected CRE group developed CRE infection. Cox regression showed that diarrhea within 3 days before CRE active surveillance and interleukin-6 ≥ 39.35pg/ml within 24 hours of CRE active surveillance were independent predictors of 90-day mortality. Summary/Conclusion:Klebsiella pneumoniae and Escherichia coli were the main strains for active CRE screening. The incidence of CRE infection was relatively elevated in detected CRE group. The active CRE surveillance may play a certain early warning role for 90-day mortality of patients, and should be implemented in the patients admitted in hematology department.Keywords: Risk factor, Drug resistance, Hematological malignancy
P1180: BURKITT INTERNATIONAL PROGNOSTIC INDEX EVALUATED IN PATIENTS TREATED WITH R-GMALL PROTOCOL
Authors: Giuliana Rizzuto, Federico Mazzon, Chiara Pavoni, Anna Maria Barbui, Silvia Ferrari, Giuseppe Gritti, Anna Grassi, Federico Lussana, Tamara Intermesoli, Alessandro Rambaldi
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Burkitt Lymphoma and Leukemia (BL) are highly aggressive lymphoid malignancies. High cure rates are reported with dose-intense chemotherapy regimens derived from pediatric leukemia regimens. Prognostic Index for Burkitt Lymphoma (BL-IPI) was derived from the real-world and extensively stratify the probability to achieve a complete response to induction treatment but is validated mostly on patients receiving inductions treatment such as R-daEPOCH o R-CODox-M/R-IVAc (T. Intermesoli, Haematol 2013 Nov 11; Adam J. Olszewski et al. JCO 2021 Apr 1; 39(10): 1129–1138). Aims: This retrospective observational analysis aims to validate BL-IPI in patients affected by BL and treated with the GMALL BALL/NHL 2002 protocol (Hoelzer D et al, Blood. 2014 Dec 18; 124(26): 3870–3879). Methods: Between December 2002 and December 2022, 151 patients with BL were enrolled in the study. The diagnosis of Burkitt lymphoma was based on histological examination according to the World Health Organization (WHO) 2016 criteria including the Burkitt-like subtype. Burkitt leukemia was diagnosed when the bone marrow analysis showed more than 25% infiltration by Burkitt-type blasts. Patients aged 55 years and younger received the full dose GMALL program with courses A–C. Patients with stage III–IV disease or mediastinal and extra-nodal involvement received a total of six courses, whereas patients with stage I–II disease were scheduled for four cycles. Patients aged over 55 years received courses A and B only, with reduced drug doses. Fit patients older than 55 years of age could be treated with the full intensity protocol if judged appropriate by the treating physician. Results: In this cohort 151 patients with BL were stratified according to BL-IPI based on age ⩾ 40 years, performance status ⩾ 2, serum lactate dehydrogenase > x3 upper limit of normal, and CNS involvement that were confirmed as factors with an independent prognostic value. There were significant differences in overall survival (OS) between patients with high, intermediate, and low risk. According to the BL-IPI, the 5-year OS was 100%, 80%, and 53% for low, intermediate, and high risk, respectively (P=0.001) (Figure A). Summary/Conclusion: To sum up, in our cohort of patients receiving R-GMALL regimen the BL-IPI was confirmed to be a significant risk stratification model. In our experience, R-GMALL has been demonstrated to be a very effective and safe program for patients with BL. However, similarly to what observed with R-CODox-M/R-IVAc, the R-GMALL regimen was not able to overcome the negative impact of high BL-IPI which remains associated with a suboptimal outcome.Keywords: Lymphoma therapy, B cell lymphoma, High-grade non-Hodgkins-lymphoma, Burkitt’s lymphoma
PB1918: HIGH BAX/BCL-2 RATIO IS ASSOCIATED WITH GOOD PROGNOSIS AND BETTER SURVIVAL IN PATIENTS WITH B CELL CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Nesrine Helaly
Journal: HemaSphere (2023)

Topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research Background: Chronic lymphocytic leukemia (CLL) is a clinically heterogenous disease characterized by the accumulation of mature appearing lymphocytes in the blood, marrow, lymph nodes and spleen. There is considerable heterogeneity in CLL in terms of cellular biology, molecular genetics and prognosis. Bcl-2 family of antiapoptotic (Bcl-2, Bcl-xl, Mcl-1) and proapoptotic (Bax, Bak, BAD) proteins are critical regulators of apoptosis in CLL and its deregulated function is involved in the pathogenesis and progression of CLL. Aims: Determination of Bax/Bcl-2 ratio as a predictive tool to recognize CLL patients’ outcome and prognosis to decide the time and type of therapy. Methods: This prospective study was carried out on 100 patients with newly diagnosed CLL. Bax and Bcl-2 expression in peripheral blood were measured by flow-cytometry. The association of Bax/Bcl-2 ratio with CLL laboratory markers, Rai stage, overall survival (OS) and progression-free survival (PFS) at 18 months was investigated. The sensitivity and specificity of Bax/Bcl-2 in predicting survival was evaluated. Results: The best cut-off value of Bax/Bcl-2 ratio to predict the survival, detected by receiver operating characteristic (ROC) curve, was 1.2 with 80 % sensitivity and 60.86 % specificity. A ratio of ≤1.20 was detected in 78 % of patients and was associated with worse prognosis. A lower Bax/Bcl-2 ratio was associated with higher modified Rai stage at time of diagnosis and a significantly shorter both OS (64.1 % versus 90.9 %, p < 0.026) and PFS (66.7 % versus 90.9 %, p < 0.031) at 18 months. In multivariate analysis, Bax/Bcl-2 ≤ 1.2 was an independent prognostic factor for overall survival, (p = 0.025) Summary/Conclusion: Lower Bax/Bcl-2 ratios were associated with worse prognosis as evidenced by lower OS and PFS in CLL patients. It was also associated with markers of high tumor burden and unfavorable prognostic markers. Recognition of patients with low Bax/Bcl-2 ratio would make them good candidates for the novel Bcl-2 inhibitory targeted chemotherapy to avoid resistance to the traditional therapy.Keywords: B-CLL, Chronic lymphocytic leukemia, Bax, BCL2
P1286: MIXED CHIMAERISM IS ASSOCIATED WITH POORER LONG-TERM FAILURE-FREE SURVIVAL AMONG APLASTIC ANAEMIA PATIENTS RECEIVING HLA-MATCHED DONOR TRANSPLANTATION
Authors: Zhengli Xu, Lanping Xu, Xiaojun Huang
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established curative option for patients with severe aplastic anaemia (SAA). Until now, none of the published studies have evaluated the association between mixed chimaerism (MC) and long-term failure free survival (FFS). Aims: The study was designed to evaluate the adverse effects of mixed chimaerism on survival outcomes and to assess the ability of different factors to predict MC in SAA patients after HLA-matched donor transplantation. Methods: A retrospective study was conducted in 103 consecutive SAA patients who received matched related (MRD) or unrelated donor (MUD) transplantation. Results: The cumulative incidences of mixed chimaerism were 17.8 ± 0.2% and 25.0 ± 0.8% in the MRD and MUD cohorts, respectively (P = 0.432). Patients with mixed chimaerism had significantly poorer 10-year failure-free survival (FFS) than those with donor chimaerism (35.0% vs. 87.0%, P < 0.001). A multivariable model identified independent adverse predictors of mixed chimaerism, including patient age and ferritin level at transplantation. The incidences of mixed chimaerism were 62.5%, 30.8% and 5.4% in the high- (2 factors), intermediate- (1 factor) and low-risk (0 factor) groups, respectively (P < 0.001). The corresponding FFS rates were 37.5%, 75.3% and 83.6%, respectively (P = 0.018), at the final follow-up. Summary/Conclusion: Our analysis has shown that mixed chimaerism led to poor FFS among SAA recipients post HLA-matched donor transplantation. Our refined predictive model was able to predict patients at high risk of developing mixed chimaerism. To further improve the prognosis, more intensive conditioning might be recommended for these high risk patients. Keywords: Anemia, Allogeneic hematopoietic stem cell transplant
P1368: NKG2A DELETION IN HUMAN NATURAL KILLER CELLS ENHANCES ANTI-TUMOR RESPONSES AND PROMOTES TUMOR INFILTRATION
Authors: Ying Gong, Wilfred Germeraad, Bo LI, Xulin Zhang, Lynn Janssen, Zongzong He, Bodeng Wu, Birgit Gijsbers, Timo Olieslagers, Gerard Bos, Lei Zheng, Roel Klein Wolterink
Journal: HemaSphere (2023)

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: Checkpoint blockage has revolutionized cancer treatment. NKG2A is an inhibitory receptor expressed by cytotoxic lymphocytes, including NK cells. In contrast to other checkpoint inhibitory antibodies, anti-NKG2A antibodies have shown only limited success. Nevertheless, recent studies highlight the importance of targeting the NKG2A pathway in cancer treatment. NK cells have seen increased attention as safe and competent effector cells for adoptive cell therapy, making it important to effectively target the NKG2A pathway. Therefore, we hypothesized that genetic deletion of KLRC1, the gene encoding NKG2A, in human NK cells is an effective and safe way to improve anti-tumor responses. Aims: We aimed to enhance anti-tumor responses of NK cells via genetic deletion of the checkpoint NKG2A in primary human NK cells. Methods: Here, we designed a Cas9-based strategy to efficiently delete KLRC1 from primary human NK cells. We then used cell lines, primary human cancer cells and tumor xenograft models to determine the effects of NKG2A genetic deletion versus NK cells alone and antibody-based blockade. Results: NKG2A-deficient NK cells showed normal proliferation, only minor transcriptional changes related to enhanced NK cell activation and maintained their phenotype and licensing status. Genetic deletion of NKG2A fully bypassed HLA-E inhibition and further enhanced NK cell activity against various tumor cell lines, thereby outperforming anti-NKG2A antibodies. In combination with antibody-coating of tumor cells to induce antibody-dependent cellular cytotoxicity, genetic deletion of NKG2A independently promoted cytotoxicity against multiple cell lines. NKG2A-deficient NK cells outperformed NKG2A antibody blockage in an assay with primary AML and ALL samples from 11 donors. Lastly, we compared untreated human NK cells, NK cells combined with anti-NKG2A antibodies and NKG2A-deficient NK cells in breast cancer and multiple myeloma xenograft models. Here, found that NKG2A-deficient NK cells best controlled tumor growth, probably explained by the observed higher cytokine production levels and better infiltration of the tumors by NK cells. Summary/Conclusion: Thus, Cas9-mediated targeting of NKG2A is an effective way to enhance the anti-tumor capacity of human NK cells via direct cytotoxicity and antibody-dependent cellular cytotoxicity. Moreover, NKG2A deletion promotes tumor infiltration via mechanisms yet to be uncovered. This technique is easily amenable to adoptive cell therapy in the clinical setting, where NKG2A deletion will promote anti-tumor responses and help NK cells to better infiltrate and persist in an inhibitory tumor microenvironment. Keywords: NK cell, Adoptive immunotherapy, Cellular therapy
P700: THE MECHANISM OF SETD2 IN MESENCHYMAL STEM CELLS REGULATED UBA5 IN MDS ERYTHROID DIFFERENTIATION
Authors: Roujia Wang, Chunkang Chang
Journal: HemaSphere (2023)

Background: The mouse model confirmed that Setd2 was involved in MDS ineffective hematopoiesis, but the mechanism is still unclear. Previous research found that after the targeted knockout of Setd2 in MSC, the differentiation of bone marrow hematopoietic stem progenitor cells was blocked, the erythroid and myeloid cells showed pathological development. Aims: To test the hypothesis that Setd2 affects the erythroid differentiation of MDS hematopoietic stem progenitor cells through the role of Uba5. Methods: We will use the NHD13 mice and MDS cell lines with the targeted knockout of Setd2 in MSC to clarify the regulatory effect of Setd2 on Uba5 and its molecular mechanism, downstream signal pathway and bone marrow microenvironment changes through WB, FCM, immunohistochemistry, RNASeq, mass spectrometry and other means. Results: Compared with NHD13 mice, MSC targeted knockout NHD13 mice turned to Leukemia faster, and peripheral blood showed a series of signs such as increased white blood cells, decreased hemoglobin, and decreased platelets. Bone marrow showed blocked development of erythroid, granulocytic, and lymphocytic lineages, and abnormal differentiation of hematopoietic stem progenitor cells. However, after knockout, the MSC itself of mice also changed in shape and function, which eventually promoted the further damage of hematopoietic cells.We searched for the downstream potential target protein Uba5 through the method of protein chip, successfully verified its expression and its relationship with erythroid development, and proposed the hypothesis that Setd2 affects the erythroid differentiation of MDS hematopoietic stem progenitor cells through the role of Uba5 and S100A9. Summary/Conclusion: This study is the first time to explore the new mechanism of ineffective hematopoiesis of MDS from the point of MSC-mediated inflammatory microenvironment change, and provide new ideas for the treatment of MDS. Keywords: Myelodysplastic syndrome
PB1721: CD27 EXPRESSION IN CHILDREN WITH B CELL LYMPHOID MALIGNANCIES AND HEMOPHAGOCYTIC LYMPH HISTIOCYTOSIS IN RELATION TO EBV STATUS: A PILOT STUDY
Authors: Nihal Hussien, Iman Ahmed Ragab, Hoda Ezz Elarab Abdelwahab, Mona Ahmed Ismail, Esraa Mohamed Abd el Raouf Wahba
Journal: HemaSphere (2023)

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: Epstein Barr Virus Infection (EBV) is associated with significant morbidity and mortality in immunocompromised patients causing a wide spectrum of EBV associated immunopathologic conditions including lymphoproliferative disorders, hemophagocytic lymphohistocytosis (HLH) and malignancy.The CD27/CD70 axis has a critical role in EBV immune surveillance. The clinical and immunological features of CD27 deficiency in severe EBV remain obscure because only few patients have been identified Aims: Evaluation of the frequency of CD27 deficiency in B cell lymphoid malignancy and HLH and to study its relation to EBV positivity. Methods: A pilot study included twenty one patients diagnosed with B cell lymphoid malignancy and HLH aged 4-10 years old (median 6 years) were enrolled. History with emphasis on preexisting disease for malignancy like immunodeficiency or autoimmune disease, family history of similar conditions or sibling death, history of blood transfusion was taken then hematology. EBV status was determined by detection of EBV nuclear antigen 1 (EBNA1) IgG by enzyme linked immune sorbent assay (ELISA) and by detection of EBV DNA via real time quantitative polymerase chain reaction (PCR) then quantification of CD27 on total lymphocytes and on CD3 by flowcytometry was performed. Results: Patients with positive EBNA-1 IgG (n=12) has significantly low percentage of CD27 expression on CD3 cells compared EBNA-1 negative ones (P=0.028). However there was no significant difference in lymphocytes CD27 expression between EBV PCR positive and negative patients The percentage of CD27 on lymphocytes showed a significant positive correlation with total leucocytic count and triglycerides level (p=0.033 and 0.037 respectively) and a significant negative correlation with the fibrinogen level (p=0.037) while absolute CD27 on lymphocytes was negatively correlated with age and fibrinogen level (p=0.007, p<0.001). The titre of EBV-EBNA-1 Ig G had a significant negative correlation with total serum Ig G and Ig M (p<0.001,p =0.001 respectively) and a significant positive correlation with serum ferritin in HLH patients (p<0.001). EBV PCR copy number shows a significant negative correlation with absolute lymphocytic count and hemoglobin level of the studied patients (p=0.019). Summary/Conclusion: A preliminary data shows an underlying CD27 deficiency on CD3 may be associated with chronic and not recent EBV infection in children with B cell lymphoid malignancy. The study will be pursued to get a larger sample size as a high frequency of EBV positivity is noted in this studied patients Keywords: B cell acute lymphoblastic leukemia, Hemophagocytic Lymphohistiocytosis (HLH), EBV, CD27
P824: LNCRNA SNHG15 BINDS DDX5 TO INDUCE R-LOOP-BASED DNA DAMAGE REPAIR TO PROMOTE BTZ RESISTANCE IN MULTIPLE MYELOMA
Authors: Lan Yao, Tingting LI, Jingjing Guo, Hongyong Zhang, Qiuling Wu
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: So far, the introduction of immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies has extended survival of multiple myeloma (MM) patients, but ultimately the majority of patients will get disease progression and subsequent relapses. However, the molecular basis of myeloma resistance still has not been fully understood. Increased DNA repair impairment and chromosomal instability (CIN) were newly identified mechanisms of tumor resistance, highlighting potential implications for resistance and potential therapeutic targets. Aims: This study was aimed to clarify the oncogenic role of lncRNA SNHG15 in myeloma progression and how lncRNA SNHG15 accelerates drug resistance via regulating DNA repair impairment and CIN in MM. Methods: RT-qPCR and western blot assays were used to demonstrated the expression of lncRNA SNHG15 and DDX5 in MM samples and cell lines. The biological effects of lncRNA SNHG15 in MM were evaluated by cell viability assay, EdU incorporation assay, flow cytometry, tumor xenograft model, western blot and so on. The binding between lncRNA SNHG15 and DDX5 was confirmed by pulldown assay and RIP-assay. DSB repair was identified by γH2AX immunofluorescence staining. R-loop formation was displayed by DNA-RNA immunoprecipitation (DRIP) and CO-IP using the S9.6 anti-R-loop antibody. Results: LncRNA SNHG15 was elevated in MM patients and myeloma cell lines, and was closely correlated with poor outcomes. In vitro and in vivo experiments showed that depletion of SNHG15 inhibited MM cells proliferation and tumor xenograft growth, sensitized cell to BTZ, and induced apoptosis in MM cells, while overexpression of lncRNA SNHG15 exhibited opposite effects. Moreover, lncRNA SNHG15 depletion weakened the repair of DNA double-strand breaks, as evidenced by reduced phosphorylation of the histone variant H2A.X (γH2AX). SNHG15 was found to accumulate in the nuclei of MM cells, where it interacted with RNA helicase DDX5 to promote the accumulation of RNA-DNA hybrids (R-loops) along chromosomes. Pulldown and RNA immunoprecipitation (RIP) assays confirmed the interaction between SNHG15 and DDX5. DRIP-qPCR assay and CO-IP demonstrated that lncRNA SNHG15 depletion decreased abnormal DDX5-dependent R-loop formation, which evoked CIN. Collectively, lncRNA SNHG15 and DDX5 are promising prognostic and therapeutic targets of MM. Summary/Conclusion: LncRNA SNHG15 is required for continued proliferation and drug resistance of myeloma cells through regulating DDX5-dependent R-loops, revealing the pro-oncogenic nature of lncRNA SNHG15 and identifying it as a promising therapeutic target of myeloma. Keywords: Chromosomal instability, Resistance, Myeloma, Epigenetic
P1565: INCIDENCE OF PNEUMOCYSTIS JIROVECII PNEUMONIA IN PATIENTS WITH B-LINEAGE LYMPHOMA RECEIVING CHEMOTHERAPY CONTAINING RITUXIMAB
Authors: Xiping Xiping Liang, Renzhi Hu, Yao Liu, Chaoyu Wang
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening infection in a wide range of HIV patients, and has been increasingly reported in non-HIV patients who are immunocompromised as a result of chemotherapy therapy. Rituximab is a monoclonal antibody which enhances the treatment efficacy of B-lineage lymphomas. It may be associated with compromise of immunity and subsequent opportunistic infections. Aims: Our objective was to determine the incidence of and risk factors for PJP infection in B-lineage lymphoma patients treated with chemotherapy containing rituximab. Methods: The medical records of 1027 B-lineage lymphoma patients who received rituximab between Jan 2019 and Jan 2021 were retrospectively evaluated. Patients were divided into two groups: patients with PJP and patients with PJP. The incidence rate of PJP and risk factors for PJP were evaluated. Results: This single-center, there were 989 adult patients receiving rituximab, from which there were 22 patients with PJP. The median patient age was 54.3 years (range 30–77) and 12 (54.5%) were female with PJP. Most patients received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (n = 791, 80.0%), and rituximab plus bendamustine was the second chemotherapy. And 725 (73.3%) patients completed four cycles and 606 (61.3%) patients completed six cycles. The cumulative incidence of PJP was 2.1%, after the start of rituximab (n = 22). Prior chemotherapy of lymphocyte count, cycles of rituximab and CD4 were associated with the development of PJP (p = 0.04). Patient’s treatment with rituximab plus liposome doxorubicin seems easier to have PJP but did not statistically significant. Summary/Conclusion: Patients who had low lymphocyte count prior chemotherapy, four cycles of rituximab, and low CD4 were more likely had a pneumocystis infection. This study showed that PCP and may help guide prevention of PJP during rituximab treatment in patients and required further investigation.Keywords: Rituximab, B cell lymphoma